Submissions for variant NM_000391.4(TPP1):c.1058C>A (p.Thr353Asn)

gnomAD frequency: 0.00008  dbSNP: rs145966505

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000437106	SCV000522722	likely pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30283815, 31283065, 34598035, 33356800)
Ambry Genetics	RCV002313067	SCV000847692	uncertain significance	Inborn genetic diseases	2022-03-09	criteria provided, single submitter	clinical testing	The c.1058C>A (p.T353N) alteration is located in exon 8 (coding exon 8) of the TPP1 gene. This alteration results from a C to A substitution at nucleotide position 1058, causing the threonine (T) at amino acid position 353 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000437106	SCV001496873	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 353 of the TPP1 protein (p.Thr353Asn). This variant is present in population databases (rs145966505, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with TPP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 382690). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPP1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genomic Medicine Lab, University of California San Francisco	RCV001375972	SCV001572967	uncertain significance	Neuronal ceroid lipofuscinosis 2	2020-01-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049548	SCV005683685	likely pathogenic	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2024-01-31	criteria provided, single submitter	clinical testing